rs1256143

Variant names:

• chr14-64444909-T-A
• rs1256143
• NM_005956.4:c.2178+175T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64444909-T-A
• chr14-64444909-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005956.4(MTHFD1):​c.2178+175T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 7 publications found

Genes affected

MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

MTHFD1 Gene-Disease associations (from GenCC):

• combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000258824 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	NM_005956.4	MANE Select	c.2178+175T>A		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.2178+175T>A		intron	N/A	NP_001351766.1	F5H2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.2178+175T>A		intron	N/A	ENSP00000498336.1	P11586
	MTHFD1	ENST00000545908.6	TSL:2	c.2178+175T>A		intron	N/A	ENSP00000438588.2	F5H2F4
	MTHFD1	ENST00000900031.1		c.2259+175T>A		intron	N/A	ENSP00000570090.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 523270 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 281628

African (AFR) AF: 0.00 AC: 0 AN: 14894

American (AMR) AF: 0.00 AC: 0 AN: 31714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17008

East Asian (EAS) AF: 0.00 AC: 0 AN: 30812

South Asian (SAS) AF: 0.00 AC: 0 AN: 56698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2324

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 307064

Other (OTH) AF: 0.00 AC: 0 AN: 28560

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 39572

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.090
DANN	Benign	0.37
PhyloP100		-1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1256143; hg19: chr14-64911627;